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A Study of ISIS 416858 Administered Subcutaneously to Participants With End-Stage Renal Disease (ESRD) on Hemodialysis (EMERALD)

Primary Purpose

End-stage Renal Disease (ESRD)

Status
Completed
Phase
Phase 2
Locations
Spain
Study Type
Interventional
Intervention
ISIS 416858
Placebo
Sponsored by
Ionis Pharmaceuticals, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for End-stage Renal Disease (ESRD)

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

• End stage renal disease maintained on outpatient hemodialysis at a healthcare center for > 3 months from screening with hemodialysis at least 3 times per week for a minimum of 9 hours per week of prescribed treatment time and plan to continue this throughout the study.

Exclusion Criteria:

  • Participants with a history of major medical event (previous acute coronary syndrome, stroke or transient ischemic attack or systemic thromboembolic event) within 3 months of screening, major surgery within 3 months of screening, or new major physical examination finding except for documented atrial fibrillation
  • Active bleeding within the past 3 months from screening or documented bleeding diathesis (excluding uremia), coagulopathy, or recent prolonged compression time at arteriovenous fistula

  • Screening values of:

    • Platelet count < 150,000 cells per millimeter cube (cells/mm^3)
    • < 180,000 cells/mm^3 for platelet function/activation subgroup
    • International normalized ratio (INR) > 1.4
    • Activated partial thromboplastin time (aPTT) > upper limit of normal (ULN)
    • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 x ULN
    • Total bilirubin > ULN
    • Factor XI (FXI) activity < 0.3 units per milliliter (U/mL)
  • Malignancy within 5 years, except basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated. Participants with malignancies that have been treated with curative intent and which have no reoccurrence within 5 years may also be eligible if approved by Sponsor Medical Monitor.

  • Within 6 months prior to screening, have any of the following:

    • More than 3 episodes of severe hypoglycemia requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions
    • One event of hypoglycemia in which the participant required hospitalization
    • Recurrent syncope and recurrent hypotension in the inter-dialytic period requiring intervention
  • Planned major surgery in the next 6 months, including participants receiving kidney transplant or participants that anticipate changing dialysis modality (i.e. hemodialysis to peritoneal dialysis)
  • Concomitant use of anticoagulant/antiplatelet agents (e.g., warfarin, dabigatran, rivaroxaban, clopidogrel) that may affect coagulation (except low dose aspirin (≤ 100 mg/day) during Treatment and Post-treatment Evaluation Periods is not allowed. Stable does of heparins during dialysis are permitted
  • Uncontrolled hypertension as judged by the Investigator. Participants with a pre- or post-dialysis blood pressure (BP) that is > 180 millimeters of mercury (mmHg) on at least 3 of last 5 dialysis treatments.

Sites / Locations

  • Ionis Investigative Site
  • Ionis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Placebo Comparator

Experimental

Experimental

Experimental

Arm Label

Placebo

Cohort A: ISIS 416858, 200 mg

Cohort B: ISIS 416858, 250 mg

Cohort C: ISIS 416858, 300 mg

Arm Description

Participants received placebo, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.

Participants received ISIS 416858, 200 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.

Participants received ISIS 416858, 250 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.

Participants received ISIS 416858, 300 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.

Outcomes

Primary Outcome Measures

Number of Participants With Major Bleeding (MB) and Clinically Relevant Non-Major Bleeding (CRNMB)
MB was defined as one of the following: Fatal bleeding; symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular if in a major joint, or pericardial, or intramuscular with compartment syndrome, clinically overt bleeding leading to transfusion of greater than or equal to (>=) 2 units of packed red blood cells or whole blood or a fall in hemoglobin of 20 grams per liter (g/L) (1.24 millimoles per liter [mmol/L]) or more within 24 hours. CRNMB was defined as overt bleeding not meeting the criteria for MB but that resulted, in either medical examination, intervention, or had clinical consequences for a participant.

Secondary Outcome Measures

Full Information

First Posted
November 13, 2017
Last Updated
December 22, 2022
Sponsor
Ionis Pharmaceuticals, Inc.
Collaborators
Bayer
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1. Study Identification

Unique Protocol Identification Number
NCT03358030
Brief Title
A Study of ISIS 416858 Administered Subcutaneously to Participants With End-Stage Renal Disease (ESRD) on Hemodialysis
Acronym
EMERALD
Official Title
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of ISIS 416858 (IONIS-FXIRX, an Antisense Inhibitor of Factor XI), Administered Subcutaneously to Patients With End-Stage Renal Disease on Hemodialysis
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Completed
Study Start Date
December 26, 2017 (Actual)
Primary Completion Date
July 10, 2019 (Actual)
Study Completion Date
July 10, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ionis Pharmaceuticals, Inc.
Collaborators
Bayer

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
No

5. Study Description

Brief Summary
Evaluation of safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of ISIS 416858 for up to 204 participants with ESRD receiving chronic hemodialysis as assessed by FXI activity reduction.
Detailed Description
Evaluation of safety, PK, and PD of ISIS 416858 (Dose # 1, Dose #2 and Dose #3 once weekly) as compared to placebo as assessed by FXI activity reduction.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
End-stage Renal Disease (ESRD)

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
213 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Participants received placebo, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.
Arm Title
Cohort A: ISIS 416858, 200 mg
Arm Type
Experimental
Arm Description
Participants received ISIS 416858, 200 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.
Arm Title
Cohort B: ISIS 416858, 250 mg
Arm Type
Experimental
Arm Description
Participants received ISIS 416858, 250 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.
Arm Title
Cohort C: ISIS 416858, 300 mg
Arm Type
Experimental
Arm Description
Participants received ISIS 416858, 300 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.
Intervention Type
Drug
Intervention Name(s)
ISIS 416858
Other Intervention Name(s)
IONIS-FXIRx
Intervention Description
Subcutaneous injection
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
0.9% sterile saline, Riboflavin
Intervention Description
Subcutaneous injection
Primary Outcome Measure Information:
Title
Number of Participants With Major Bleeding (MB) and Clinically Relevant Non-Major Bleeding (CRNMB)
Description
MB was defined as one of the following: Fatal bleeding; symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular if in a major joint, or pericardial, or intramuscular with compartment syndrome, clinically overt bleeding leading to transfusion of greater than or equal to (>=) 2 units of packed red blood cells or whole blood or a fall in hemoglobin of 20 grams per liter (g/L) (1.24 millimoles per liter [mmol/L]) or more within 24 hours. CRNMB was defined as overt bleeding not meeting the criteria for MB but that resulted, in either medical examination, intervention, or had clinical consequences for a participant.
Time Frame
Up to Day 260
Other Pre-specified Outcome Measures:
Title
Percent Change From Baseline in Activated Partial Thromboplastin Time (aPTT)
Time Frame
Baseline (Day 1) up to Day 260
Title
Percent Change From Baseline in Factor XI (FXI) Activity
Time Frame
Baseline (Day 1) up to Day 260
Title
Number of Participants With Laboratory Abnormalities Related to Platelet Count
Description
Participants were assessed based on pre-defined criteria in the protocol for platelet count abnormality: 100 - less than (<)140, 75 - <100, 50 - <75, 25 - <50 and < 25 thousands per cubic millimeter (K/mm^3) based on investigator's discretion.
Time Frame
Up to Day 260
Title
Number of Participants With Laboratory Abnormalities - Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST)
Description
Participants were assessed based on pre-defined criteria in protocol for abnormality in ALT and AST values: Confirmed ALT (serum glutamic pyruvic transaminase [SGPT]); greater than (>) 3*Upper limit of normal range (ULN), >5*ULN and confirmed AST (serum glutamic-oxaloacetic transaminase [SGOT]); >3*ULN and >5*ULN. A confirmed value was based on a consecutive lab value within 7 days of the initial value. If that value was in the same or worse category the initial value was confirmed. If the consecutive value was in a better category then the initial value was confirmed using the consecutive value category. If there were multiple results on the same day, no matter from the same lab vendor or different lab vendors, then the worst value was used in the analysis. Abnormality in laboratory parameter was based on investigator's discretion.
Time Frame
Up to Day 260
Title
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Time Frame
Up to Day 260
Title
Percent Change From Baseline in Factor XI (FXI) Antigen Levels
Time Frame
Baseline (Day 1) up to Day 260

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: • End stage renal disease maintained on outpatient hemodialysis at a healthcare center for > 3 months from screening with hemodialysis at least 3 times per week for a minimum of 9 hours per week of prescribed treatment time and plan to continue this throughout the study. Exclusion Criteria: Participants with a history of major medical event (previous acute coronary syndrome, stroke or transient ischemic attack or systemic thromboembolic event) within 3 months of screening, major surgery within 3 months of screening, or new major physical examination finding except for documented atrial fibrillation Active bleeding within the past 3 months from screening or documented bleeding diathesis (excluding uremia), coagulopathy, or recent prolonged compression time at arteriovenous fistula Screening values of: Platelet count < 150,000 cells per millimeter cube (cells/mm^3) < 180,000 cells/mm^3 for platelet function/activation subgroup International normalized ratio (INR) > 1.4 Activated partial thromboplastin time (aPTT) > upper limit of normal (ULN) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 x ULN Total bilirubin > ULN Factor XI (FXI) activity < 0.3 units per milliliter (U/mL) Malignancy within 5 years, except basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated. Participants with malignancies that have been treated with curative intent and which have no reoccurrence within 5 years may also be eligible if approved by Sponsor Medical Monitor. Within 6 months prior to screening, have any of the following: More than 3 episodes of severe hypoglycemia requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions One event of hypoglycemia in which the participant required hospitalization Recurrent syncope and recurrent hypotension in the inter-dialytic period requiring intervention Planned major surgery in the next 6 months, including participants receiving kidney transplant or participants that anticipate changing dialysis modality (i.e. hemodialysis to peritoneal dialysis) Concomitant use of anticoagulant/antiplatelet agents (e.g., warfarin, dabigatran, rivaroxaban, clopidogrel) that may affect coagulation (except low dose aspirin (≤ 100 mg/day) during Treatment and Post-treatment Evaluation Periods is not allowed. Stable does of heparins during dialysis are permitted Uncontrolled hypertension as judged by the Investigator. Participants with a pre- or post-dialysis blood pressure (BP) that is > 180 millimeters of mercury (mmHg) on at least 3 of last 5 dialysis treatments.
Facility Information:
Facility Name
Ionis Investigative Site
City
Santiago De Compostela
State/Province
A Coruna
ZIP/Postal Code
15706
Country
Spain
Facility Name
Ionis Investigative Site
City
Alcalá De Henares
State/Province
Madrid
ZIP/Postal Code
28805
Country
Spain

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

A Study of ISIS 416858 Administered Subcutaneously to Participants With End-Stage Renal Disease (ESRD) on Hemodialysis

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